2-Piperidone → 1-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-piperidin-2-one

HRID 1773900Notes

Reaction equation

HRID 1773900 reaction equation
[Na].[C:2]1(=[O:8])[NH:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][C:21]4[CH:37]=[CH:36][CH:35]=[CH:34][C:22]=4[CH:23]3[O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:17]=2[CH3:38])=[CH:12][CH:11]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1.CO>[CH3:38][C:17]1[N:18]2[C:24]([CH:23]([O:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[CH2:20][CH2:19]2)=[N:25][C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[O:8])=[CH:11][CH:12]=1

Participants

8

Reactant 4

HCID 126652-PiperidoneHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 5360545SodiumHCID 726953822-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

Product 1

HCID 867039761-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-piperidin-2-one

Reagents, catalysts & solvents 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 887MethanolSolventHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

In a screw-capped vial are added MeOH (3.5 mL) and sodium metal (2 mg). After 10 min, valerolactam (16 mg, 0.16 mmole) is added. The solvent is removed under reduced pressure. To the residual solid are added 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (50 mg, 0.107 mmole), Pd(dba)2 (4.9 mg, 5.3 μmole), Xantphos (6.2 mg, 10.6 μmole), toluene (0.7 mL). The flask is evacuated and filled with argon and the reaction mixture is heated at 110° C. overnight. Water is added and pH adjusted to 10 with a few drops of 1N NaOH. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (100:0:0) to (96.5:3.5:0.35) to give 1-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-piperidin-2-one.

Workup

  1. customThe solvent is removed under reduced pressure
  2. customThe flask is evacuated
  3. additionfilled with argon
  4. additionWater is added
  5. extractionThe aqueous phase is extracted three times with CH2Cl2
  6. dry with materialThe organic phase is dried over magnesium sulphate
  7. filtrationfiltered
  8. customthe solvent is removed under reduced pressure
  9. customThe residue is purified by silica gel chromatography

Sources & evidence

ORD record
ord-06f33a0cf9ee4fe7aa7a4ae8e370a6fd
Source dataset
uspto-grants-2016_02
Patent number
US09255101B2

Reaction notes

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